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Amylin Pharmaceuticals, Inc. (O.G.K., M.S.F., E.G., S.H., T.A.B., K.T., D.K., M.A., Y.W., A.D.B.), San Diego, California 92121; and University of North Carolina School of Medicine (J.B.B.), Chapel Hill, North Carolina 27599
Address all correspondence and requests for reprints to: Alain D. Baron, M.D., Amylin Pharmaceuticals, Inc., 9373 Towne Centre Drive, San Diego, California 92121. E-mail: abaron{at}amylin.com.
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Despite the introduction of a number of novel agents for the treatment of type 2 diabetes, glucose control in this population remains unsatisfactory because average hemoglobin A1c (HbA1c) values well above 8% are reported in many epidemiologic studies (2). Moreover, many therapies have limiting side effects such as weight gain, hypoglycemia, and edema, and have restrictions for use (3). Results from the United Kingdom Prospective Diabetes Study (UKPDS) indicate that ß-cell failure is progressive and relentless (4) despite therapy with insulin, sulfonylurea, or biguanide agents (5). In contrast, insulin resistance does not appear to progress in parallel with ß-cell failure (6). Consistent with this finding, an increasing proportion of subjects in the UKPDS who were treated originally with diet management or OAAs eventually required insulin therapy for glucose control (7). No currently available therapy has been shown to slow the decline in ß-cell function in established type 2 diabetes. Taken together, these data suggest that ideal therapies for the long-term treatment of type 2 diabetes are needed to delay, arrest, or reverse declining ß-cell function (8, 9, 10, 11). Preferably, such therapies should exhibit a unique mode of action to enable additive or synergistic use with current therapies; produce no weight gain, hypoglycemia, or other limiting or unmanageable side effects; preserve or enhance ß-cell function; and reduce cardiovascular risk factors that lead to morbidity and mortality.
AC2993 (synthetic exendin-4; exenatide), a 39-amino acid peptide, potentially exhibits many of these desired features of a new antidiabetic therapy. Antidiabetic actions of AC2993 include glucose-dependent enhancement of insulin secretion (12, 13, 14); glucose-dependent suppression of inappropriately high glucagon secretion (15); slowing of gastric emptying (16), which may be paradoxically accelerated in people with diabetes (17); and reduction of food intake (18, 19). At least some of these antidiabetic actions (e.g. enhancement of insulin secretion) may be mediated by AC2993 binding to the known glucagon-like peptide-1 (GLP-1) receptor (20). These actions of AC2993 combined with its very high (>1000-fold) in vivo potency relative to native GLP-1 (21, 22) make AC2993 an attractive pharmaceutical agent. Although GLP-1 and AC2993 appear to share certain glucose-lowering actions, it is apparent that not all actions of exendin-4 are predictable based on the known pharmacology of GLP-1. For example, GLP-1 but not exendin-4 has been shown to suppress gastric acid secretion (23), and intraportal GLP-1 infusion triggers the hepatic vagal afferents but exendin-4 does not (24). The reasons for these apparent differences are yet unknown. Also, in animal (25, 26, 27) and in vitro (26, 27) models, AC2993 has been shown to promote ß-cell proliferation and neogenesis from precursor cells, thus transforming noninsulin-producing cells into insulin-producing cells. Other data obtained in animal models of insulin resistance suggest that AC2993 may also have an insulin sensitizing effect (22), although this has not yet been shown in humans (28).
The current studies were designed to examine the postprandial and fasting glucose-lowering effect of AC2993 in individuals with type 2 diabetes. To fully explore the glucose-lowering potential of AC2993, one study examining postprandial glucose control was conducted across groups exhibiting a range of disease severity based on current therapy either with diet management alone, OAA, or insulin with or without OAA. The second study was conducted to evaluate the effect of AC2993 on fasting glucose concentrations. Some of the data presented here have been previously reported in abstract form (29, 30, 31).
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Subjects and Methods |
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Eligible subjects for each study were required to have type 2 diabetes mellitus treated with diet management, any OAA, or insulin with or without OAA (study A only). OAA regimens were to have been stable for at least 6 months (study A) or 3 months (study B) before screening. Subjects were to be 18–65 yr of age; male or if female, postmenopausal or surgically sterile. In addition, subjects were to have HbA1c 12% or lower (study A) or between 7.5% and 11% (study B) at screening. Fasting blood glucose was to be less than 14.4 mmol/liter (study A) or less than 13.3 mmol/liter (study B) before starting the study. All subjects provided written informed consent before participation in these studies, which were approved by an institutional review board (University of North Carolina, Durham, NC) and conducted in accordance with the principles endorsed by the Declaration of Helsinki.
Study design
Study A: postprandial evaluations. This single-blind, placebo-controlled, two-period crossover study was designed to evaluate the effects of 0.1 µg/kg AC2993 administered sc twice daily (BID), immediately before breakfast and dinner, on postprandial glucose excursions in subjects exhibiting a range of type 2 diabetes severity. Subjects discontinued OAA treatment 14 d before d 1 of the first 5-d treatment period and did not resume OAA therapy until after study completion. Eligible subjects on insulin therapy replaced their existing regimen with a single dose of long-acting insulin each evening to achieve a fasting blood glucose value less than 10 mmol/liter for at least three consecutive days before d 1. This regimen was continued for the duration of the study. Following enrollment, subjects were admitted to an inpatient unit and divided among four groups based on baseline diabetes treatment and/or HbA1c (i.e. diabetes severity) as follows: (1) diet management alone; (2) OAA treated, HbA1c less than 8.0%; (3) OAA treated, HbA1c 8.0% or more to 12.0% or less; and (4) insulin treated with or without OAA.
Subjects received 0.1 µg/kg AC2993 BID for 5 d and placebo BID for 5 d during consecutive treatment periods separated by a 2- to 3-d interim. Each treatment (0.1 µg/kg AC2993 or placebo) was injected sc BID, before breakfast and dinner. Subjects were discharged from the inpatient unit during the interim period and no study treatment was given. The treatment sequence (i.e. placebo, followed by 0.1 µg/kg AC2993, or 0.1 µg/kg AC2993, followed by placebo) was assigned randomly. Subjects were randomized within each diabetes severity group (described above) to achieve balanced treatment sequences within each population.
Following an overnight fast, baseline evaluations of plasma glucose, plasma insulin, and plasma glucagon were performed before study medication injection on d 1 and 5. Ten minutes following injection, subjects consumed a standardized liquid breakfast of Sustacal (Mead Johnson, Evansville, IN) (7 kcal/kg). At the same time, acetaminophen solution (20 mg/kg) was ingested, and its appearance in plasma was used as an indicator of gastric emptying rate (32). On both days, timed blood samples were drawn to evaluate concentration profiles over the following periods after injection: plasma glucose, 300 min; plasma insulin, 300 min; plasma glucagon, 180 min; and plasma acetaminophen, 300 min.
Study B: fasting evaluations. This double-blind, placebo-controlled, four-period crossover study in subjects with type 2 diabetes mellitus was designed to examine the effects of three doses of AC2993 on plasma glucose concentrations following an overnight fast. Subjects’ diabetes was treated with diet alone, metformin alone, a thiazolidinedione alone (rosiglitazone or Pioglitazone), or a combination of metformin and one of the thiazolidinediones. Subjects continued their regular regimen of specified OAA therapy during the study.
Subjects were randomly assigned to one of four treatment sequences. Each subject received three sc injections of AC2993 (0.05 µg/kg, 0.1 µg/kg, and 0.2 µg/kg) and one of placebo in a predetermined random order. The placebo dose volume was the same volume as that calculated for an individual subject’s 0.1 µg/kg AC2993 dose. Dosing days were separated by a 1-d wash-out period.
Following an overnight fast, baseline evaluations of plasma glucose, serum insulin, and plasma glucagon were performed before injection of a single dose of study medication on d 1, 3, 5, and 7. While the subjects remained fasting, timed blood samples were collected for 8 h following study medication injection to evaluate concentration profiles of plasma glucose, serum insulin, and plasma glucagon. No treatments were administered on intervening d 2, 4, and 6.
Subjects in both studies were monitored for safety by assessment of adverse events, physical examination findings, electrocardiograms, vital signs, and laboratory values (serum chemistry, hematology, and urinalysis). For both studies, quantitation of plasma glucose, insulin, and glucagon were performed by Esoterix Laboratories (Calabasas Hills, CA) according to well established methods. Glucose was measured using the glucose/HK reagent set (Roche Diagnostics, Indianapolis, IN, cat. no. 1876899) for glucose analysis based on the glucose hexokinase methodology (33, 34). Insulin was measured using a two-site immunochemiluminometric assay. Glucagon was measured using a double-antibody RIA. Acetaminophen was assayed by MDS Pharma Services using an HPLC methodology (Toronto, Ontario, Canada).
Statistical methods In both studies, the pharmacodynamic parameter assessed for plasma glucose [area under the curve (AUC)(0-t)] was calculated using the incremental plasma glucose concentration curve, which was derived by subtracting the baseline glucose concentration from each subsequent value. The baseline value for plasma glucose was calculated as the mean of the -15 min and -5 min time points. Pharmacodynamic parameters for insulin, glucagon, and acetaminophen [AUC(0-t)] were calculated from the respective plasma or serum concentration profiles and were loge transformed before analysis. Pharmacodynamic evaluations in both studies are relative to the time of dose administration. Evaluable subjects were defined as those who completed the majority of treatment periods with sufficient data to allow reliable evaluation of the pharmacodynamic parameters.
Pharmacodynamic analyses were performed using an ANOVA or mixed-effect model that included terms for sequence, period, and treatment as fixed effects and subject-within-sequence as a random effect. Sequence (i.e. carryover) was tested using the subject-within-sequence error term, and period and treatment were tested using the intrasubject error term. The least square means and SEM were derived from the ANOVA or mixed-effect model for both AC2993 and placebo treatment regimens. The critical P value for statistical significance was P less than 0.05. Unless otherwise specified, data are presented as mean ± SEM.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Study A: postprandial evaluation.
The study population consisted of 24 subjects with type 2 diabetes mellitus. The population was 71% male, 58% Hispanic, 33% Caucasian, and 8% Black. Subjects’ mean age was 55.8 ± 2.1 yr, mean BMI was 28.8 ± 0.8 kg/m2, and mean weight was 82.9 ± 3.3 kg. Subjects were assigned to four groups, as follows: group 1, four subjects; group 2, six subjects; group 3, eight subjects; and group 4, six subjects. Demographic and baseline characteristics were similar among groups (Table 1
). All subjects completed the study; four were excluded from the pharmacodynamic evaluations because of inadequate consumption of Sustacal as specified in the study protocol. By definition, the plasma insulin analysis did not include the four subjects who received insulin therapy during the study.
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). For OAAs, eight patients were taking metformin and one rosiglitazone. One subject was excluded from the pharmacodynamic evaluations because of inadequate exposure to study medication. Effect of AC2993 on postprandial plasma glucose, plasma insulin, plasma glucagon, serum triglyceride, and plasma acetaminophen concentrations (study A)
Postprandial plasma glucose.
Significant reductions in mean postprandial plasma glucose concentrations were noted during the 300 min following treatment with 0.1 µg/kg AC2993, compared with placebo (Fig. 1; P < 0.05). During treatment with placebo on d 5, mean plasma glucose concentrations increased from 170.3 ± 9.1 mg/dl (9.5 ± 0.5 mmol/liter) at baseline to a peak value of 289.0 ± 17.0 mg/dl (16.0 ± 0.9 mmol/liter) at 120 min after dosing and decreased to 175.5 ± 14.9 mg/dl (9.7 ± 0.8 mmol/liter) at 300 min. In contrast, mean plasma glucose concentrations decreased from 159.5 ± 10.0 mg/dl (8.9 ± 0.6 mmol/liter) at baseline to a nadir of 126.4 ± 11.6 mg/dl (7.0 ± 0.6 mmol/liter) at 180 min and 177.8 ± 14.8 mg/dl (9.9 ± 0.8 mmol/liter) at 300 min during treatment with 0.1 µg/kg AC2993 (d 5). Results were similar on d 1 (Fig. 1A) and d 5 (Fig. 1B), and a similar effect was observed in each of the four study groups (Fig. 2).
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Postprandial plasma insulin.
Increases in mean postprandial plasma insulin concentrations were significantly reduced during the 300 min following 0.1 µg/kg AC2993 treatment, compared with placebo (Fig. 3). On d 5, mean plasma insulin concentrations in the placebo group increased from 8.4 ± 1.3 µU/ml (58.3 ± 9.0 pmol/liter) at baseline to 86.3 ± 28.0 µU/ml (599.4 ± 194.5 pmol/liter) at 120 min and then decreased to 15.8 ± 3.1 µU/ml (109.7 ± 22.2 pmol/liter) at 300 min. In contrast, mean plasma insulin concentrations increased from 9.1 ± 1.5 µU/ml (63.9 ± 10.4 pmol/liter) at baseline to 38.4 ± 9.8 µU/ml (266.7 ± 68.1 pmol/liter) at 90 min during treatment with 0.1 µg/kg AC2993 and decreased only slightly at 180 min, 240 min, and 300 min to 25.4 ± 6.6 µU/ml (176.4 ± 47.2 pmol/liter), 31.1 ± 6.3 µU/ml (216.0 ± 43.8 pmol/liter), and 33.8 ± 5.9 µU/ml (234.7 ± 41.0 pmol/liter), respectively. On d 5, the insulin AUC(0–300min) was reduced 35% following 0.1 µg/kg AC2993 treatment, compared with placebo (P = 0.0011). Results were similar on d 1 and d 5.
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). During treatment with placebo on d 5, mean plasma glucagon concentrations increased from 94.9 ± 8.9 pg/ml (94.9 ± 8.9 ng/liter) at baseline to 173.9 ± 22.5 pg/ml (173.9 ± 22.5 ng/liter) at 60 min and then decreased slowly to 122.7 ± 18.1 pg/ml (122.7 ± 18.1 ng/liter) at 180 min. In contrast, mean plasma glucagon concentrations were comparatively unchanged throughout the 180-min postprandial sampling period after treatment with 0.1 µg/kg AC2993 relative to the mean baseline concentration (98.9 ± 7.2 pg/ml; 98.9 ± 7.2 ng/liter). Values varied less than 5–6% [-3.3 to 5.8 pg/ml (-3.3 to 5.8 ng/liter) on d 5]. Consistent with these findings, the glucagon AUC(0–180min) was significantly lower on d 5 following 0.1 µg/kg AC2993 treatment, compared with placebo (P = 0.0123). Results were similar on d 1 and d 5.
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), consistent with slowed gastric emptying. The difference in acetaminophen AUC(0–300min) was statistically significant (P < 0.0001). Results were similar on d 1 and d 5.
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Fasting plasma glucose.
All three doses of AC2993 (0.05 µg/kg, 0.1 µg/kg, and 0.2 µg/kg) markedly reduced plasma glucose concentrations, compared with placebo in the fasting state during the 8-h period of observation (Fig. 5A; P < 0.0001). There was a trend indicating AC2993 at a dose of 0.1 µg/kg lowered plasma glucose more than 0.05 µg/kg; however, there were insufficient patients dosed in each group to do a statistical comparison. No additional effect on glucose was observed at 0.2 µg/kg, compared with 0.1 µg/kg. The mean fasting plasma glucose nadir occurred between 3 and 4 h after administration of AC2993. At 3 h post dose, the mean fasting plasma glucose concentrations were 137.6 ± 9.4, 120.6 ± 8.6, and 108.9 ± 6.7 mg/dl (6.0 ± 0.4, 6.7 ± 0.5, and 7.6 ± 0.5 mmol/liter) for AC2993 0.2 µg/kg, 0.1 µg/kg, and 0.05 µg/kg doses, respectively, compared with 195.0 ± 13.2 mg/dl (10.8 ± 0.8 mmol/liter) for placebo. At 4 h post dose, the mean fasting plasma glucose concentrations were 137.2 ± 9.6, 119.5 ± 5.4, and 117.4 ± 6.3 mg/dl (7.6 ± 0.6, 6.6 ± 0.3, and 6.5 ± 0.3 mmol/liter) for AC2993 0.05 µg/kg, 0.1 µg/kg, and 0.2 µg/kg doses, respectively, compared with 187.9 ± 12.1 mg/dl (10.4 ± 0.7 mmol/liter) for placebo.
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Fasting serum insulin.
The data demonstrate a dose-dependent rise in serum insulin concentrations within the first 3 h after AC2993 administration, compared with placebo (Fig. 5B; P < 0.001). In addition, there was a statistically significant, AC2993 dose-dependent increase in fasting insulin for AUC0–3 h (P < 0.0001). In sharp contrast, placebo treatment exhibited relatively stable insulin concentrations throughout the 8-h period of observation. The rise and peak of serum insulin concentrations following AC2993 administration coincided with the rapid decline of fasting glucose concentrations. After 3–4 h post dose and coincident with reaching the glucose concentration nadir, mean serum insulin concentrations returned to baseline, with little difference observed among the active treatments and placebo. The peak mean incremental serum insulin concentrations, in order from highest to lowest AC2993 dose, were 25.6 ± 4.5 µU/ml (177.8 ± 31.3 pmol/liter; 0.2 µg/kg), 20.0 ± 2.9 µU/ml (138.9 ± 20.1 pmol/liter; 0.1 µg/kg), 8.8 ± 1.5 µU/ml (61.1 ± 10.4 pmol/liter; 0.05 µg/kg), and 0.9 ± 1.3 µU/ml (6.3 ± 9.0 pmol/liter; placebo). Insulin AUC(0–8 h) and Cmax values for all AC2993 treatments increased in an apparently dose-dependent manner, compared with placebo. AUC(0–8 h) values increased 92% (0.2 µg/kg), 44% (0.1 µg/kg), and 19% (0.05 µg/kg), compared with placebo.
Fasting plasma glucagon.
Within the first 3 h after AC2993 treatment, mean fasting plasma glucagon concentrations appeared to be markedly suppressed, compared with placebo (Fig. 4B); however, because of small sample size, this effect did not reach statistical significance. After 3 h post dose and coincident with reaching the glucose concentration nadir, little difference in fasting plasma glucagon concentrations were observed among the AC2993 treatments and placebo. Inspection of individual subject data did not reveal suppression of fasting plasma glucagon beyond 3 h post dose by AC2993 treatments.
Safety. No clinically meaningful differences were noted in the physical examination findings, electrocardiograms, vital signs, or clinical laboratory measures following treatment with 0.05 µg/kg, 0.1 µg/kg, 0.2 µg/kg AC2993 or placebo. Of 123 adverse events reported during the two studies, 79 (64%) were classified by the investigator as related to study medication, and most were classified as mild in intensity and transient. The most frequent of these events were headache (27 events), vomiting (18 events), and nausea (17 events). No serious events were reported, and no subject withdrew from the studies because of an adverse event.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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AC2993 has been reported to exhibit a number of acute and longer-term actions in animal models that may account for its glucose-lowering effects in humans. Insulinotropism (14), suppression of glucagon secretion (15), and slowing of gastric emptying (16) are principal acute actions. The longer-term actions of AC2993 include weight reduction (22), enhanced insulin sensitivity (22), and increased ß-cell mass (25, 27). Chief among the acute actions is glucose-dependent insulinotropism, i.e. the amplification of ß-cell insulin release when glucose concentrations are above the normal range but not when glucose concentrations are below the normal range (13, 14). The end result of glucose-dependent insulinotropism is to increase the gain of glucose-insulin secretion coupling while maintaining the physiologic glucose-sensing control mechanisms. This action of AC2993 contrasts with the action of available insulin secretagogues or hypoglycemic agents, such as sulfonylureas, which increase insulin secretion regardless of the glucose concentration (38) and thus have the potential to induce hypoglycemia (5).
The glucose-dependent insulinotropism exhibited by AC2993 is best illustrated by the data obtained in the fasting state (Fig. 5B). These data show a dose-dependent effect of AC2993 on enhancing glucose-dependent insulinotropism while the prevailing glucose concentration is elevated (first 3 h) and a gradual fall in insulin secretion with reestablishment of near basal insulinemia when the prevailing glucose concentration decreases to the near normal range (beyond the first 3 h). Since AC2993 concentrations remained elevated throughout the course of the assessment consistent with the long circulating half-life of AC2993 (39), the reduction in insulin beyond 3 h does not reflect a simple loss of AC2993 effect because of lower circulating concentrations of AC2993. Because of the multiple acute glucose-lowering actions of AC2993 operative in the postprandial period, it is not possible to ascertain the net individual contribution of glucose-dependent insulinotropism, suppression of glucagon secretion, or slowing of gastric emptying on postprandial glucose control. In contrast to the fasting state, postprandial insulin concentrations were actually lower after AC2993 treatment, compared with placebo (Fig. 3). However, relative to the extent of reduced glucose concentrations (Fig. 1), postprandial insulinemia may, in fact, be enhanced. Thus, glucose-dependent insulinotropism appears to be an important mechanism for reduction of both fasting and postprandial glucose concentrations.
Glucagon concentrations were reduced by AC2993 in both the fasting and postprandial states (Fig. 4). This observation supports the notion that suppression of glucagon secretion is not merely related to the slowing of nutrient presentation to the small intestine (gastric emptying). Moreover, suppression of glucagon was observed over the range of diabetes severity (not shown), demonstrating that this effect of AC2993 is robust. Given the well documented elevated fasting and postprandial glucagon concentrations in patients with type 2 diabetes (40) and the known action of glucagon to maintain hepatic glucose output (41), it is reasonable to expect that glucagon suppression by AC2993 contributed to the overall effect of lowering glucose concentrations in both the fasting and postprandial periods. Similar to insulin concentrations, glucagon concentrations also returned toward baseline beyond 3 h post injection during the fasting state, coincident with reaching nadir glucose concentrations. Because the changes in concentrations of insulin and glucagon are coincident, the effects of AC2993 to enhance insulin secretion and suppress glucagon secretion may be considered glucose dependent. Currently available secretagogues and exogenous insulin administration do not suppress the paradoxical postprandial rise of glucagon concentrations observed in patients with diabetes (42). This results in an inappropriately low insulin:glucagon ratio in the portal vein (to a greater extent than with exogenous insulin) contributing to sustained rates of excess hepatic glucose production (43). Thus, by virtue of its effects to enhance endogenous insulin and lower glucagon secretion, AC2993 would tend to reestablish a more physiologic and favorable portal vein ratio of insulin to glucagon, compared with the effect of currently available agents.
Given the initially flat postprandial glucose profile, it is likely that gastric emptying is a major contributor to glucose control early in the postprandial period but less so in the late postprandial period. Delivery of nutrients from the stomach to the small intestine is a critical contributor to postprandial glucose excursions (44). Indeed, patients who have undergone gastrectomy exhibit postprandial hyperglycemia in spite of apparently normal ß-cell function and fasting euglycemia (45). Whether gastric emptying rates are slow, normal, or accelerated in patients with diabetes without severe autonomic neuropathy is controversial (17). One of the main confounders in understanding the pathophysiology of gastric emptying in diabetes is hyperglycemia itself because elevated glucose concentrations in nondiabetics slow gastric emptying rate (46). Thus, a normal gastric emptying rate in the face of hyperglycemia may be considered pathophysiologic because it is relatively accelerated, compared with an expected normal slowing in the face of hyperglycemia.
Gastric emptying as assessed by acetaminophen appearance rates in plasma after oral administration was slowed by AC2993 (Table 2). Meal-entrained endogenous enteropancreatic hormones such as cholecystokinin, amylin, and GLP-1 also slow gastric emptying, attesting to the importance of this function for overall nutrient assimilation (47).
AC2993 exhibited sustained activity with respect to postprandial glucose lowering, glucagon suppression, and slowing of gastric emptying over five consecutive days across the spectrum of severity of type 2 diabetes (Fig. 2). AC2993 was well tolerated overall with headache, nausea, and vomiting as the main adverse events. It is noteworthy that nausea tended to dissipate over the 5 d of exposure to AC2993.
In conclusion, AC2993 can acutely and markedly reduce both fasting and postprandial glucose concentrations in patients with type 2 diabetes exhibiting a wide range of disease severity. This overall acute antihyperglycemic effect is mediated by several mechanisms. In the fasting state, both glucose-dependent enhancement of insulin and suppression of glucagon secretion are predominant while in the postprandial period slowing of gastric emptying is additionally operative. These combined actions recapitulate many of the known actions of GLP-1 on glucose-lowering in this patient population (48, 49). This robust overall antidiabetic effect warrants further development of AC2993 for the treatment of patients with type 2 diabetes.
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Acknowledgments |
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Footnotes |
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Abbreviations: AUC, Area under the curve; BID, administered twice daily; GLP-1, glucagon-like peptide-1; HbA1c, hemoglobin A1c; OAA, oral antidiabetic agent.
Received October 3, 2002.
Accepted March 24, 2003.
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 N. A. Sherry, W. Chen, J. A. Kushner, M. Glandt, Q. Tang, S. Tsai, P. Santamaria, J. A. Bluestone, A.-M. B. Brillantes, and K. C. Herold Exendin-4 Improves Reversal of Diabetes in NOD Mice Treated with Anti-CD3 Monoclonal Antibody by Enhancing Recovery of {beta}-Cells Endocrinology, November 1, 2007; 148(11): 5136 - 5144. [Abstract] [Full Text] [PDF]
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D. Kim, L. MacConell, D. Zhuang, P. A. Kothare, M. Trautmann, M. Fineman, and K. Taylor Effects of Once-Weekly Dosing of a Long-Acting Release Formulation of Exenatide on Glucose Control and Body Weight in Subjects With Type 2 Diabetes Diabetes Care, June 1, 2007; 30(6): 1487 - 1493. [Abstract] [Full Text] [PDF]
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B. E. Dunning and J. E. Gerich The Role of {alpha}-Cell Dysregulation in Fasting and Postprandial Hyperglycemia in Type 2 Diabetes and Therapeutic Implications Endocr. Rev., May 1, 2007; 28(3): 253 - 283. [Abstract] [Full Text] [PDF]
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S. T. Haines Emerging Treatments for Patients With Type 2 Diabetes The Diabetes Educator, May 1, 2007; 33(Supplement_5): 105S - 110S. [Full Text] [PDF]
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 B. Zinman, B. J. Hoogwerf, S. Duran Garcia, D. R. Milton, J. M. Giaconia, D. D. Kim, M. E. Trautmann, and R. G. Brodows The Effect of Adding Exenatide to a Thiazolidinedione in Suboptimally Controlled Type 2 Diabetes: A Randomized Trial Ann Intern Med, April 3, 2007; 146(7): 477 - 485. [Abstract] [Full Text] [PDF]
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 T. H Claus, C. Q Pan, J. M Buxton, L. Yang, J. C Reynolds, N. Barucci, M. Burns, A. A Ortiz, S. Roczniak, J. N Livingston, et al. Dual-acting peptide with prolonged glucagon-like peptide-1 receptor agonist and glucagon receptor antagonist activity for the treatment of type 2 diabetes J. Endocrinol., February 1, 2007; 192(2): 371 - 380. [Abstract] [Full Text] [PDF]
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K. G. Murphy, W. S. Dhillo, and S. R. Bloom Gut Peptides in the Regulation of Food Intake and Energy Homeostasis Endocr. Rev., December 1, 2006; 27(7): 719 - 727. [Abstract] [Full Text] [PDF]
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 D. Hinnen, L. L. Nielsen, A. Waninger, and P. Kushner Incretin Mimetics and DPP-IV Inhibitors: New Paradigms for the Treatment of Type 2 Diabetes J Am Board Fam Med, November 1, 2006; 19(6): 612 - 620. [Abstract] [Full Text] [PDF]
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D. Soon, P. A. Kothare, H. Linnebjerg, S. Park, E. Yuen, K. F. Mace, and S. D. Wise Effect of exenatide on the pharmacokinetics and pharmacodynamics of warfarin in healthy asian men. J. Clin. Pharmacol., October 1, 2006; 46(10): 1179 - 1187. [Abstract] [Full Text] [PDF]
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B. K. Yoo, D. M. Triller, and D. J. Yoo Exenatide: A New Option for the Treatment of Type 2 Diabetes Ann. Pharmacother., October 1, 2006; 40(10): 1777 - 1784. [Abstract] [Full Text] [PDF]
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 R. D. Wideman, I. L. Y. Yu, T. D. Webber, C. B. Verchere, J. D. Johnson, A. T. Cheung, and T. J. Kieffer Improving function and survival of pancreatic islets by endogenous production of glucagon-like peptide 1 (GLP-1) PNAS, September 5, 2006; 103(36): 13468 - 13473. [Abstract] [Full Text] [PDF]
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L. L. Baggio, D. Holland, J. Wither, and D. J. Drucker Lymphocytic Infiltration and Immune Activation in Metallothionein Promoter-Exendin-4 (MT-Exendin) Transgenic Mice Diabetes, June 1, 2006; 55(6): 1562 - 1570. [Abstract] [Full Text] [PDF]
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P. D. van Poelje, S. C. Potter, V. C. Chandramouli, B. R. Landau, Q. Dang, and M. D. Erion Inhibition of Fructose 1,6-Bisphosphatase Reduces Excessive Endogenous Glucose Production and Attenuates Hyperglycemia in Zucker Diabetic Fatty Rats Diabetes, June 1, 2006; 55(6): 1747 - 1754. [Abstract] [Full Text] [PDF]
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 S. Park, X. Dong, T. L. Fisher, S. Dunn, A. K. Omer, G. Weir, and M. F. White Exendin-4 Uses Irs2 Signaling to Mediate Pancreatic beta Cell Growth and Function J. Biol. Chem., January 13, 2006; 281(2): 1159 - 1168. [Abstract] [Full Text] [PDF]
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L Marenah, P R Flatt, D F Orr, C Shaw, and Y H A Abdel-Wahab Skin secretions of Rana saharica frogs reveal antimicrobial peptides esculentins-1 and -1B and brevinins-1E and -2EC with novel insulin releasing activity J. Endocrinol., January 1, 2006; 188(1): 1 - 9. [Abstract] [Full Text] [PDF]
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N. N. Zammitt and B. M. Frier Hypoglycemia in Type 2 Diabetes: Pathophysiology, frequency, and effects of different treatment modalities Diabetes Care, December 1, 2005; 28(12): 2948 - 2961. [Full Text] [PDF]
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F. Fehse, M. Trautmann, J. J. Holst, A. E. Halseth, N. Nanayakkara, L. L. Nielsen, M. S. Fineman, D. D. Kim, and M. A. Nauck Exenatide Augments First- and Second-Phase Insulin Secretion in Response to Intravenous Glucose in Subjects with Type 2 Diabetes J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 5991 - 5997. [Abstract] [Full Text] [PDF]
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 E. M Sinclair and D. J. Drucker Proglucagon-Derived Peptides: Mechanisms of Action and Therapeutic Potential Physiology, October 1, 2005; 20(5): 357 - 365. [Abstract] [Full Text] [PDF]
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T. Talsania, Y. Anini, S. Siu, D. J. Drucker, and P. L. Brubaker Peripheral Exendin-4 and Peptide YY3-36 Synergistically Reduce Food Intake through Different Mechanisms in Mice Endocrinology, September 1, 2005; 146(9): 3748 - 3756. [Abstract] [Full Text] [PDF]
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P. A. Kothare, D. K. W. Soon, H. Linnebjerg, S. Park, C. Chan, A. Yeo, M. Lim, K. F. Mace, and S. D. Wise Effect of Exenatide on the Steady-State Pharmacokinetics of Digoxin J. Clin. Pharmacol., September 1, 2005; 45(9): 1032 - 1037. [Abstract] [Full Text] [PDF]
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 A. Aziz, G. H. Anderson, A. Giacca, and F. Cho Hyperglycemia after protein ingestion concurrent with injection of a GLP-1 receptor agonist in rats: a possible role for dietary peptides Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2005; 289(3): R688 - R694. [Abstract] [Full Text] [PDF]
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 C. A Schnabel The incretin mimetic, exenatide: a novel treatment option for type 2 diabetes The British Journal of Diabetes & Vascular Disease, July 1, 2005; 5(4): 227 - 235. [Abstract] [PDF]
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D. M. Kendall, M. C. Riddle, J. Rosenstock, D. Zhuang, D. D. Kim, M. S. Fineman, and A. D. Baron Effects of Exenatide (Exendin-4) on Glycemic Control Over 30 Weeks in Patients With Type 2 Diabetes Treated With Metformin and a Sulfonylurea Diabetes Care, May 1, 2005; 28(5): 1083 - 1091. [Abstract] [Full Text] [PDF]
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R. A. DeFronzo, R. E. Ratner, J. Han, D. D. Kim, M. S. Fineman, and A. D. Baron Effects of Exenatide (Exendin-4) on Glycemic Control and Weight Over 30 Weeks in Metformin-Treated Patients With Type 2 Diabetes Diabetes Care, May 1, 2005; 28(5): 1092 - 1100. [Abstract] [Full Text] [PDF]
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E. Blase, K. Taylor, H.-y. Gao, M. Wintle, and M. Fineman Pharmacokinetics of an Oral Drug (Acetaminophen) Administered at Various Times in Relation to Subcutaneous Injection of Exenatide (Exendin-4) in Healthy Subjects J. Clin. Pharmacol., May 1, 2005; 45(5): 570 - 577. [Abstract] [Full Text] [PDF]
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 K. Dungan and J. B. Buse Glucagon-Like Peptide 1-Based Therapies for Type 2 Diabetes: A Focus on Exenatide Clin. Diabetes, April 1, 2005; 23(2): 56 - 62. [Abstract] [Full Text] [PDF]
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B. R. Gedulin, S. E. Nikoulina, P. A. Smith, G. Gedulin, L. L. Nielsen, A. D. Baron, D. G. Parkes, and A. A. Young Exenatide (Exendin-4) Improves Insulin Sensitivity and {beta}-Cell Mass in Insulin-Resistant Obese fa/fa Zucker Rats Independent of Glycemia and Body Weight Endocrinology, April 1, 2005; 146(4): 2069 - 2076. [Abstract] [Full Text] [PDF]
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 O. G. Kolterman, D. D. Kim, L. Shen, J. A. Ruggles, L. L. Nielsen, M. S. Fineman, and A. D. Baron Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus Am. J. Health Syst. Pharm., January 15, 2005; 62(2): 173 - 181. [Abstract] [Full Text] [PDF]
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S. V Joy, P. T Rodgers, and A. C Scates Incretin Mimetics as Emerging Treatments for Type 2 Diabetes Ann. Pharmacother., January 1, 2005; 39(1): 110 - 118. [Abstract] [Full Text] [PDF]
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J. B. Buse, R. R. Henry, J. Han, D. D. Kim, M. S. Fineman, A. D. Baron, and for the Exenatide-113 Clinical Study Group Effects of Exenatide (Exendin-4) on Glycemic Control Over 30 Weeks in Sulfonylurea-Treated Patients With Type 2 Diabetes Diabetes Care, November 1, 2004; 27(11): 2628 - 2635. [Abstract] [Full Text] [PDF]
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Z. T. Bloomgarden Gut-Derived Incretin Hormones and New Therapeutic Approaches Diabetes Care, October 1, 2004; 27(10): 2554 - 2559. [Full Text] [PDF]
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C. F. Deacon Therapeutic Strategies Based on Glucagon-Like Peptide 1 Diabetes, September 1, 2004; 53(9): 2181 - 2189. [Abstract] [Full Text] [PDF]
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K. B. Degn, B. Brock, C. B. Juhl, C. B. Djurhuus, J. Grubert, D. Kim, J. Han, K. Taylor, M. Fineman, and O. Schmitz Effect of Intravenous Infusion of Exenatide (Synthetic Exendin-4) on Glucose-Dependent Insulin Secretion and Counterregulation During Hypoglycemia Diabetes, September 1, 2004; 53(9): 2397 - 2403. [Abstract] [Full Text] [PDF]
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 C M. B Edwards GLP-1: target for a new class of antidiabetic agents? J R Soc Med, June 1, 2004; 97(6): 270 - 274. [Full Text] [PDF]
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D. A. D'Alessio and T. P. Vahl Glucagon-like peptide 1: evolution of an incretin into a treatment for diabetes Am J Physiol Endocrinol Metab, June 1, 2004; 286(6): E882 - E890. [Abstract] [Full Text] [PDF]
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) on d 1 (A) and d 5 (B) (n = 20). Conversion factor: mmol/liter = 0.05555 mg/dl.
), or 0.2 µg/kg AC2993 (
) on d 5 (n = 12). Conversion factor: ng/liter = pg/ml.
), or 0.2 µg/kg AC2993 (
) administered at t = 0 (n = 12). Conversion factors: glucose: mmol/liter = 0.05555 mg/dl; insulin: pmol/liter = 6.945 µU/ml.